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  • On the other hand it is quite possible


    On the other hand, it is quite possible that strychnine-sensitive glycine sites are responsible for mediating the anticonvulsant effects of GlyT1 inhibitors. Strychnine, which acts as an antagonist at these sites, is a well-known as a convulsant drug, and elevation of endogenous glycine levels at these sites would be expected to produce an anticonvulsant effect. This possibility is supported by the recent report that GlyT1 inhibitors produce more sustained increases in glycine levels in caudal rather than cortical 29 8 mg areas (Perry et al., 2008). However, at the doses used in our study we did not observe any of the locomotor activity or gross behavioural effects reported by Perry et al. (2008), indicating that the anticonvulsant effects we observed are not due to any non-specific motor effects. Additional studies will be needed to investigate this question of the exact mechanism of action involved in the anticonvulsant effects of GlyT1 inhibitors. In conclusion, for the first time we have shown that inhibition of glycine uptake with several GlyT1 inhibitors is associated with anticonvulsant efficacy in the MEST test in the rat. Since several GlyT1 inhibitors are already in clinical development for the treatment of schizophrenia and related disorders (Shim et al., 2008, Javitt, 2009), such compounds could also find future therapeutic uses as anticonvulsant drugs.
    Experimental procedures
    Schizophrenia affects approximately 1% of the world’s population; however, current therapies are associated with unwanted side affects and/or do not provide sufficient relief across all symptom domains. Based on pre-clinical models and clinical data, the -methyl--aspartate receptor (NMDAr) hypofunction hypothesis of schizophrenia correlates disease symptomology with glutamatergic neurotransmission dysfunction. Hence, increasing NMDAr neurotransmission represents a promising approach for the development of antipsychotics. Direct NMDAr agonists and elevated levels of its endogenous ligand glutamate are known to be neurotoxic. In contrast, targeted elevation of synaptic glycine, an NMDAr coagonist, represents a viable opportunity for neurotransmission enhancement. Synaptic glycine levels are regulated by glycine transporter 1 (GlyT1), making the blockade of GlyT1-mediated glycine reuptake an attractive method for enhancing NMDAr neurotransmission. Considerable effort has been invested in discovering GlyT1 inhibitors and the area has been extensively reviewed., Herein, we describe a novel series of GlyT1 inhibitors as a potential therapy for schizophrenia. Our lead-finding strategy relied on a virtual screen to identify compounds that had pharmacophoric similarity with validated GlyT1 inhibitors from the literature. The computational screening model employed in-house developed 2D topological fingerprints. They encoded the distribution of various pharmacophore features (e.g., aromaticity, lipophilicity, H-bond donors and acceptors, positive and negative charges) up to distances of 12 bonds. Compounds that met our similarity criteria to literature inhibitors were clustered and a representative sample of members from each cluster was filtered for suitable CNS-drug like properties (e.g., molecular weight, lipophilicity) and the absence of toxic or reactive functional groups. A final set of 15,000 candidates was submitted for biological screening. These were tested in a GlyT1 uptake inhibition assay at 10μM. The most potent hit was 4-chlorobenzenesulfonamide (IC 1.4±0.1μM) which contains elements that are related to some reported GlyT1 inhibitors. For example aryl sulfonamides also appear in the 1,3-diaminopropanol series from GSK, and a related benzyl linked amine comprises the basic region in SSR504734 from Sanofi. Intrigued by the potential for rapid structural modification, we embarked on a campaign to scope the structure–activity relationship of the phenethyl diamine scaffold of with respect to GlyT1 inhibition. Compounds were prepared from commercially available 2-amino-2-phenylethanamines via sulfonylation or acylation. Where said phenylethanamines could not be purchased, they were obtained via a Strecker reaction between an amine and aldehyde followed by an alane reduction., For example, as shown in , the aldehyde used to prepare compound was derived from 4-mercaptobenzoic acid () by first alkylating with propyl iodide and then oxidizing with Oxone® to afford sulfone . Reduction of the ester to the corresponding alcohol was followed by oxidation to give aldehyde . A Strecker reaction between azepane and provided the corresponding nitrile, which was reduced with alane to furnish amine . Subsequent sulfonylation yielded . If amide analogs of were desired, they were obtained via acylation (ArCOCl, DIPEA, CHCl) or amide coupling (ArCOOH, HOBt, TBTU, DIPEA, DMF).